Abuse-deterrent pharmaceutical compositions of opioids and other drugs

ABSTRACT

An abuse-deterrent pharmaceutical composition has been developed to reduce the likelihood of improper administration of drugs, especially drugs such as opioids. In a preferred embodiment, a drug is modified to increase its lipophilicity. In some embodiments the modified drug is homogeneously dispersed within spherical microparticles composed of a material that is either slowly soluble or not soluble in water. In some embodiments the drug containing microparticles or drug particles are coated with one or more coating layers, where at least one coating is water insoluble and/or organic solvent insoluble. The abuse-deterrent composition retards the release of drug, even if the physical integrity of the formulation is compromised (for example, by chopping with a blade or crushing) and the resulting material is placed in water, snorted, or swallowed. However, when administered as directed, the drug is slowly released from the composition as the composition is passes through the GI tract.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 12/112,993,filed Apr. 30, 2008, which is a divisional of U.S. Ser. No. 10/614,866filed Jul. 7, 2003, which claims priority to U.S. Ser. No. 60/393,876filed Jul. 5, 2002 entitled “Abuse-Resistant Formulations of Oxycontinand Other Drugs” by Alexander M. Klibanov, Stephen L. Buchwald, TimothyM. Swager, and Whe-Yong Lo; U.S. Ser. No. 60/436,523 filed Dec. 23, 2002by Alison B. Fleming, Roman V. Rariy, Alexander M. Klibanov, Whe-YongLo, and Jane Hirsh; U.S. Ser. No. 60/443,226 filed Jan. 28, 2003 by JaneHirsh, Alison B. Fleming, Alexander M. Klibanov, and Whe-Yong Lo; U.S.Ser. No. 60/463,514 filed Apr. 15, 2003 by Jane C. Hirsh, Alison B.Fleming, Roman V, Rariy, Stephen L. Buchwald, and Timothy M. Swager; andU.S. Ser. No. 60/463,518 filed Apr. 15, 2003 by Jane C. Hirsh, Alison B.Fleming and Roman V. Rariy.

This application also is a continuation-in-part of Ser. No. 12/112,937,filed Apr. 30, 2008, which is a continuation-in-part of U.S. Ser. No.10/614,866, filed Jul. 7, 2003, which claims priority to U.S. Ser. No.60/393,876 filed Jul. 5, 2002; U.S. Ser. No. 60/436,523 filed Dec. 23,2002; U.S. Ser. No. 60/443,226 filed Jan. 28, 2003; U.S. Ser. No.60/463,514 filed Apr. 15, 2003; and U.S. Ser. No. 60/463,518 filed Apr.15, 2003 and a continuation-in-part of U.S. Ser. No. 11/149,867, filedJun. 10, 2005, which claims priority to U.S. Ser. No. 60/579,191, filedJun. 12, 2004.

FIELD OF THE INVENTION

The present invention is generally in the field of pharmaceuticalcompositions, and specifically compositions that are designed to reducethe potential for improper administration of drugs, such as thosesubject to abuse.

BACKGROUND OF THE INVENTION

Oxycodone, morphine, and other opioid analgesics are successful andtherapeutically useful medications, e.g., as pain killers, whenadministered orally. Unfortunately, they also pose a severe threat forwillful abuse due to their ability to alter mood and/or cause a sense ofeuphoria. Currently available sustained release formulations of suchdrugs, which contain a relatively large amount of drug meant to bereleased from the formulation over an extended time period, areparticularly attractive to abusers since the sustained release actioncan be destroyed by crushing or grinding the formulation. The resultingmaterial (i.e., the crushed formulation) can no longer control therelease of drug. Depending on the drug, abusers can then (1) snort thematerial, (2) swallow the material or (3) dissolve the material in waterand subsequently inject it intravenously. The dose of drug contained inthe formulation is absorbed immediately through the nasal or GI mucosa(for snorting or swallowing, respectively) or is administered in a bolusto the systemic circulation (for IV injection). These abuse methodsresult in the rapid bioavailability of relatively high doses of drug,giving the abuser a “high”. Since relatively simple methods (crushing,grinding, chewing and/or dissolution in water) can be used to transformsuch formulations into an abusable form, they provide virtually nodeterrent to a potential abuser.

For example, the FDA recently strengthened the warnings and precautionssections in the labeling of OxyContin® (oxycodone HClcontrolled-release) tablets, a narcotic drug approved for the treatmentof moderate to severe pain, because of continuing reports of abuse anddiversion. OxyContin® contains oxycodone (available in 10, 20, 40 and 80mg strengths), an opioid agonist with an addiction potential similar tothat of morphine. Opioid agonists are substances that act by attachingto specific proteins called opioid receptors, which are found in thebrain, spinal cord, and gastrointestinal tract. When these drugs attachto certain opioid receptors in the brain and spinal cord they caneffectively block the transmission of pain messages to the brain.

OxyContin® is supplied in a controlled-release dosage form and isintended to provide up to 12 hours of relief from moderate to severepain. The warning specifically states that the tablet must be takenwhole and only by mouth. When the tablet Is chewed or crushed and itscontents are swallowed, snorted into the nostrils or dissolved andsubsequently injected intravenously, the controlled release mechanism isdestroyed and a potentially lethal dose of oxycodone becomesbioavailable.

In recent years, there have been numerous reports of Oxycodone diversionand abuse in several states. For example, the DEA's Office of DiversionControl reported 700 OxyContin® thefts in the United States betweenJanuary 2000 and June 2001. Some of these reported cases have beenassociated with serious consequences including death. According to areport from the Abuse and Mental Health Services Administration, Resultsfrom the 2004 National Survey on Drug Use and Health: National Findings(Rockville, Md.: US Dept. of Health and Human Services, Office ofApplied Studies, 2005, p. 50), in 2004, the number of new non-medicalusers of OxyContin® was 615,000, with an average ago at first use of24.5 years. Comparable data on past year Oxycontin initiation are notavailable for prior years, but calendar year estimates of Oxycontin®initiation show a steady increase in the number of initiates from 1995,the year this product was first available, through 2003

Oxycodone is a controlled substance in Schedule II of the ControlledSubstances Act (CSA), which is administered by the Drug EnforcementAdministration (DEA). Despite the fact that Schedule IX provides themaximum amount of control possible under the CSA for approved drugproducts, in practice it is difficult for law enforcement agencies tocontrol the diversion or misuse of legitimate prescriptions. Althoughabuse, misuse, and diversion are potential problems for all opioids;including Oxycodone, opioids are a very important part of the medicalarmamentarium for the management of pain when used appropriately underthe careful supervision of a physician.

Currently available formulations for such drugs are designed for oraladministration but are vulnerable to alterations in their dissolutioncharacteristics by physical manipulation of the formulation as discussedabove. Such formulations are also vulnerable due to the inherently highwater solubility of the API contained therein. Because of their nature,these formulations do not prevent or deter improper methods ofadministration such as chewing, injection and snorting. This representsa serious problem given the large number of legitimate prescriptionswritten in the US; for example, the medical use of opioids within the USincreased 400% from 1996 to 2000. The problems with abuse aresignificant and longstanding, and efforts to design new abuse-resistantor abuse-deterrent formulations have been largely unsuccessful.

U.S. Pat. No. 3,980,766 to Shaw et at (“Shaw”), U.S. Pat. No. 4,070,494to Hoffmeister et al. (“Hoffmeister”), and U.S. Pat. No. 6,309,668 toBastin et al. (“Bastin”) describe formulations designed to prevent theinjection of compositions meant for oral administration.

Shaw describes the incorporation of an ingestible solid which causes arapid increase in viscosity upon concentration of an aqueous solutionthereof.

Hoffmeister describes the incorporation of a non-toxic, water gelablematerial in an amount sufficient to render the drug resistant to aqueousextraction.

Bastin describes a tablet for oral administration containing two or morelayers containing one or more drugs and one or more gelling agentswithin separate layers of the tablet. The resulting tablet forms a gelwhen combined with the volume of water necessary to dissolve the drugallegedly reducing the extractability of the drug from the tablet.

It should be noted that although these compositions allegedly precludeabuse by injection, this approach fails to prohibit rapid dissolution ofthe drug once the dosage form is crushed into smaller particles orpieces. Thus, these formulations are vulnerable to abuse by crushing andswallowing or snorting the formulation, which are commonly reportedmethods of abuse associated with OxyContin®.

U.S. Pat. Nos. 3,773,955 and 3,966,940 to Pachter et al. describeformulations containing a combination of opioid agonists andantagonists, in which the antagonist does not block the therapeuticeffect when the admixture is administered orally, but which does notproduce analgesia, euphoria or physical dependence when administeredparenterally by an abuser.

U.S. Pat. No. 4,457,933 to Gordon et al, describes a method fordecreasing both the oral and parenteral abuse potential of stronganalgetic agents by combining an analgesic dose of the analgetic agentwith an antagonist in specific, relatively narrow ratios.

U.S. Pat. Nos. 6,277,384, 6,375,957 and 6,475,494 to Kaiko et al.describe oral dosage forms including a combination of an orally activeopioid agonist and an orally active opioid antagonist in a ratio that,when delivered orally, is analgesically effective but that is aversivein a physically dependent subject. While such a formulation may besuccessful in deterring abuse, it also has the potential to produceadverse effects in legitimate patients.

It is therefore an object of the present invention to provide apharmaceutical composition that significantly reduces the potential forimproper administration or use of drugs but which, when administered asdirected, is capable of delivering a therapeutically effective dose.

SUMMARY OF THE INVENTION

An abuse-deterrent pharmaceutical composition and methods of making andusing thereof have been developed. The compositions can be used toreduce the likelihood of improper administration of drugs, especiallydrugs prone to abuse such as oxycodone. The technology is useful for anumber of other drugs where sustained release oral delivery is desired,and there is potential for abuse if the drug dose is made immediatelyavailable for nasal, intravenous (IV) or oral administration. In apreferred embodiment, the drug is chemically modified to increase itslipophilicity and is formulated as microparticles. In other embodiments,the formulation contains lipophilic or water-insoluble materials or ismade using a process which increases the lipophilicity and/orwater-insolubility of the composition. In some embodiments, thecomposition additionally contains one or more antioxidants.

The abuse-deterrent composition retards the release of drug, even if thephysical integrity of the dosage form is compromised (for example, bychopping with a blade or crushing) and the resulting material is placedin water, snorted, or swallowed. However, when administered as directed,the drug is released slowly (typically over a period of 4-18 hours) fromthe composition by diffusion as the composition is broken down ordissolved gradually within the GI tract by a combination of surfactantaction of bile acids, mechanical erosion and/or enzymatic degradation.

In some embodiments, the individual drug-containing microparticles ordrug particles are coated With one or more independent coating layers.At least one of the coating materials is water-insoluble and/or organicsolvent-insoluble, so that in vitro degradation of the formulation willrequire more than one step. Thus, the drug is not easily extractablefrom the formulations by conventional chemical means. In contrast, whenadministered to the gastrointestinal tract via swallowing, the drug willgradually be released from the coated microparticles as a consequence ofdiffusion, the gradual break down of the formulation via surfactantaction of bile acids, mechanical erosion and/or enzymatic degradation.

The pharmaceutical composition, when administered orally, results in adesired drug release profile. The release profile provides a therapeuticeffect for an extended period of time, typically from 6 to 24 hours,preferably from 12 to 24 hours. Additional compositions are providedwhich achieve a small immediate release dose that precedes the sustainedrelease of drug. The compositions disclosed herein may optionallycontain a drug having no appreciable abuse potential.

DETAILED DESCRIPTION OF THE INVENTION

Disclosed herein are an abuse-deterrent pharmaceutical compositions andthe method of making and using the compositions.

I. Compositions

As used herein, “composition” refers to the drug dosage unit foradministration to a patient. “Composition” may also be used in referencesolely to the active ingredient, or to a formulation containing theactive ingredient.

The currently available sustained release dosage forms containingnarcotic analgesics and other drugs are subject to misuse, in part,because mechanical destruction of the dosage form exposes theencapsulated drug and allows for immediate dissolution of the drug intoaqueous media. Three properties of the dosage form that contribute tothis outcome are, (1) the high water solubility of the drug salt form;(2) the lack of protection offered by the hydrophilic and/or watersoluble excipients in the formulation; and (3) the ease with which thesurface area of the formulation is increased by simple chewing orcrushing. Susceptibility to simple methods such as chewing or crushingis particularly problematic for monolithic controlled-release dosageforms. For monolithic dosage forms, such as tablets, even splitting theunit into a few pieces (without completely crushing it) can result in adramatic increase in the dissolution rate.

In the compositions disclosed herein, one or more of these propertiesare altered in order to achieve an abuse-deterrent composition.Specifically, in the one embodiment, the drug is modified to increaseits lipophilicity which reduces its water solubility. The modified drugis then homogeneously dispersed within one or more carrier materialsthat are either slowly soluble or not soluble in water. Dispersionwithin these materials further reduces the accessibility of the drugwhen crushed and exposed to an aqueous media. In some embodiments, thedrug may be partially or fully dispersed in the carrier materials on amolecular level. The intimate mixture of modified drug and carriermaterials is subsequently formulated into microparticles, producing aformulation whose surface area is minimally influenced by chewing orcrushing.

The terms “abuse-deterrent composition” or “abuse-deterrent formulation”are used interchangeably herein to refer to compositions that reduce thepotential for improper administration of drugs but that deliver atherapeutically effective dose when administered as directed. Improperadministration includes tampering with the dosage form and/oradministering the drug by any route other than instructed. For example,for a tablet or capsule, methods of tampering with the dosage form mayinclude, but are not limited to, breaking, crushing, grinding, chewingand/or dissolving the tablet or the contents of the capsule. For oraladministration, improper administration includes administering the drugby any route other than via swallowing.

The abuse deterrent compositions preferably contain a drug modified toincrease its lipophilicity. In some embodiments, the drug ishomogenously dispersed within microparticles composed of a material thatis either slowly soluble in water or water insoluble. The compositionsmaintain the slow the release of drug if the dosage form is chopped orcrushed and the resulting material is placed in water, snorted, orswallowed since most of the drug will remain associated with orentrapped within portions of the core material of the microparticles. Inother embodiments, the drug containing microparticles or individual drugparticles are coated with one or more coating layers, where at least onecoating is water insoluble and/or organic solvent insoluble. Thecomponents of the resulting coated microparticles are not mutuallysoluble in water or organic solvents, such that no one solvent or enzymesolution is capable of dissolving the formulation in its entirety invitro. Therefore, extraction of the drug from the formulation cannot becarried out in one step. However, when administered as directed, thedrug is slowly released from the formulation via diffusion and erosionwithin the environment of the gastrointestinal tract.

A. Drugs to be Formulated

There are many drugs which can be delivered using the compositionsdescribed herein. The Controlled Substances Act (CSA), Title II of theComprehensive Drug Abuse Prevention and Control Act of 1970, places allsubstances that are regulated under existing federal law into one offive schedules based upon the substance's medicinal value, harmfulness,and potential for abuse or addiction. Drugs that are preferred includethose classified as Schedule II, III, IV and V drugs. Drugs that aremost preferable include those, like oxycodone, that are currentlyformulated as sustained or controlled release compositions, where drugrelease is intended to occur over a prolonged period of time through thegastrointestinal tract, and immediate or burst release, for example, byinhalation or injection, is undesirable. As used herein, drugs prone toabuse refer to controlled substance specified as schedule II, III, IVand V drugs,

The terms “drug”, “active agent”, and “pharmacologically active agent”are used interchangeably herein to refer to a chemical compound thatinduces a desired pharmacological, physiological effect. The terms alsoencompass pharmaceutically acceptable derivatives of those active agentsspecifically mentioned herein, including, but not limited to, salts,solvates, hydrates, complexes with one or more molecules, prodrugs,active metabolites, analogs, and the like. When the terms “activeagent”, “pharmacologically active agent” and “drug” are used, or when aparticular drug, such as oxycodone, is identified, it is to beunderstood as including the active agent per se as well aspharmaceutically acceptable salts, solvates, hydrates, complexes withone or more molecules, prodrugs, active metabolites, and analogs.

Examples of preferred drugs include, 1-phenylcyclohexylamine,1-piperidinocyclohexanecarbonitrile, alfentanil, alphacetylmethadol,alphaprodine, alprazolam, amobarbital, amphetamine, anileridine,apomorphine, aprobarbital, barbital, barbituric acid derivative,bemidone, benzoylecgonine, benzphetamine, betacetylmethadol,betaprodine, bezitramide, bromazepam, buprenorphine, butabarbital,butalbital, butorphanol, camazepam, cathine, chloral, chlordiazepoxide,clobazam, clonazepam, clorazepate, clotiazepam, cloxazolam, cocaine,codeine, chlorphentermine, delorazepam, dexfenfluramine, dextromoramide,dextropropoxyphen, dezocine, diazepam, diethylpropion, difenoxin,dihydrocodeine, dihydromorphine, dioxaphentyl butyrate, dipanone,diphenoxylate, diprenorphine, ecgonine, enadoline, eptazocine,estazolam, ethoheptazine, ethyl loflazepate, ethylmorphine, etorphine,femproponex, fencamfamin, fenfluramine, fentanyl, fludiazepam,flunitrazepam, flurazepam, glutethimide, halazepam, haloxazolam,hexalgon, hydrocodone, hydromorphone, isomethadone, hydrocodone,ketamine, ketazolam, ketobemidone, levanone, levoalphacetylmethadol,levomethadone, levomethadyl acetate, levomethorphan, levorphanol,lofentanil, loperamide, loprazolam, lorazepam, lormetazepam, lysergicacid, lysergic acid amide, mazindol, medazepam, mefenorex, meperidine,meptazinol, metazocine, methadone, methamphetamine, methohexital,methotrimeprazine, methyldihydromorphinone, methylphenidate,methylphenobarbital, metopon, morphine, nabilone, nalbuphine, nalbupine,nalorphine, narceine, nefopam, nicomorphine, nimetazepam, nitrazepam,nordiazepam, normethadone, normorphine, oxazepam, oxazolam, oxycodone,oxymorphone, pentazocine, pentobarbital, phenadoxone, phenazocine,phencyclidine, phendimetrazine, phenmetrazine, pheneridine, piminodine,prodilidine, properidine, propoxyphene, racemethorphan, racemorphan,racemoramide, remifentanil, secobarbital, sufentanil, talbutal,thebaine, thiamylal, thiopental, tramadol, trimeperidine, andvinbarbital.

In addition to the compounds above, the following scheduled drugs may beincorporated into the composition: allobarbitone, alprazolam,amylobarbitone, aprobarbital, barbital, barbitone, benzphetamine,brallobarbital, bromazepam, brotizolam, buspirone, butalbital,butobarbitone, butorphanol, camazepam, captodiame, carbromal;carfentanil, carpipramine, cathine, chloral, chloral betaine, chloralhydrate, chloralose, chlordiazepoxide, chlorhexadol, chlormethiazoleedisylate, chlormezanone, cinolazepam, clobazam, potassium clorazepate,clotiazepam, cloxazolam, cyclobarbitone, delorazepam, dexfenfluramine,diazepam, diethylpropion, difebarbamate, difenoxin, enciprazine,estazolam, ethyl loflazepate, etizolam, febarbamate, fencamfamin,fenfluramine, fenproporex, fluanisone, fludiazepam, flunitraam,flunitrazepam, flurazepam, flutoprazepam, gepirone, glutethimide,halazepam, haloxazolam, hexobarbitone, ibomal, ipsapirone, ketazolam,loprazolam mesylate; lorazepam, lormetazepam, mazindol, mebutamate,medazepam, mefenorex, mephobarbital, meprobamate, metaclazepam,methaqualone, methohexital, methylpentynol, methylphenobarbital,midazolam, milazolam, morphine, nimetazepam, nitrazepam, nordiazepam,oxazepam, oxazolam, paraldehyde, pemoline, pentabarbitone, pentazocine,pentobarbital, phencyclidine, phenobarbital, phondimetrazine,phenmetrazine, phenprobamate, phentermine, phenyacetone, pinazepam,pipradol, prazepam, proxibarbal, quazepam, quinalbaritone, secobarbital,secbutobarbitone, sibutramine, temazepam, tetrazepam, triazolam,triclofos, zalepan, zaleplon, zolazepam, zolpidem, and zopiclone.Certain compounds described herein may exist in particular geometric orstereoisomeric forms. The composition disclosed herein contemplates allsuch compounds, including cis- and trans-isomers, R- and S-enantiomers,diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof,compounds of different spacial conformations, and other mixturesthereof, as falling within the scope of the invention. Additionalasymmetric carbon atoms may be present in a substituent such as an alkylgroup. All such isomers, as well as mixtures thereof, are intended to beincluded in this invention.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, myristic, palmitic,lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxybenzoic, fumaric, tolunesulfonic, methanesulfonic, ethanedisulfonic, oxalic, and isethionic.

The pharmaceutically acceptable salts of the compounds can besynthesized from the parent compound, which contains a basic or acidicmoiety, by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins,Baltimore, Md., 2000, p. 704, the disclosure of which is herebyincorporated by reference.

Optionally, the composition described herein can further include a drughaving no appreciable abuse potential.

B. Drug Solubility Modification

In some embodiments, the solubility characteristics of a drug arealtered. Modification of the drug to produce a more lipophilicderivative serves to reduce the water solubility of the drug and thusreduce the aqueous extractability of the drug. Furthermore, if the drugis made more lipophilic, it can be solubilized in a molten fattysubstance or wax like mixture, rather than physically dispersed in aparticulate form. Solubilization of the drug enhances theabuse-deterrent properties of microparticles formulated from the mixtureas it is difficult to extract drug from an intimately dispersedcomposition. Furthermore, such a composition is capable of controllingthe release of drug, even when formulated into relatively smallmicroparticles. Microparticulate compositions, in contrast to monolithiccompositions, are inherently less susceptible to tampering by mechanismsthat are intended to increase the surface area and, consequently, therelease rate of drug (such as chewing or crushing).

The terms “lipophilic derivative” and “lipophilic drug derivative”, asused herein, refer to derivatives of the drug that are less soluble ordissolve less rapidly in water than the most soluble salt of the drug;the most soluble salt being selected from either base addition salts(for acidic drugs) or acid addition salts (for basic drugs), such as bythe addition of inorganic acids. The examples of the latter include butare not limited to hydrohalates, sulfates, and nitrates, Some of themethods that can be used to alter the drug's lipophilicity are outlinedbelow. It is understood that two or more approaches can be combined toachieve a desired solubility profile.

Methods for Increasing Lipophilicity

In one embodiment, the drug is made more lipophilic by eliminating orreducing the overall charge of the drug molecule. For example, for abasic drug, a water soluble salt (such as hydrochloride, sulfate, ormaleate) can be converted to a free base using techniques known in theart. In the case of an acidic drug, a water soluble salt (such assodium, potassium, or the like) can be converted to a free acid.

In another embodiment, the drug's lipophilicity is increased by forminga salt between a drug molecule and a charged lipophilic compound. Inthis case the lipophilicity of the resulting salt can be manipulated byvarying the lipophilicity of the counter-ion. In general, lipophilicacids or amines with chain lengths between C₅-C₃₀ are lipophiliccounter-ion candidates. Some specific examples include, but are notlimited to, linoleic acid, octanoic acid, lauric acid, stearic acid,palmitic acid, myristic acid, oleic acid, octyl amine, lauryl amine,stearyl amine, palmityl amine, linoleyl amine, and oleyl amine. Othersalts which may increase lipophilicity and, hence, lipid solubilityrelative to the parent drug compound include, but are not limited to,pectinate, tannate; phytate, salicylate, saccharinate, acesulfamate,gallate, and terephthalate salts.

In still a further embodiment, drug lipophilicity is increased viacomplexation with poorly water-soluble cyclodextrin. For example,ethylated beta-cyclodextrin has been shown to decrease aqueoussolubility of complexed drug molecules.

In another embodiment, a drug is covalently modified to increase itslipophilicity. For example, a lipophilic compound can be covalentlyattached to a drug molecule via an ester or amide linkage. Such drugderivatives are cleaved in vivo, thus releasing the. parent compound,

C. Drug Containing Microparticles

In some embodiments, the drug is formulated with a carrier material toform microparticles. As used herein, the term “microparticle” refers toa composition containing a drug dispersed within a carrier material and“coated microparticle” refers to a composition containing a drugcontaining microparticle or a drug particle coated with one or morecoating layers of material. Microparticles and coated microparticleshave a size range of 10 to 3000 microns in diameter, more preferablyfrom 10 to 1000 microns.

Within microparticles, the drug is preferably homogeneously dispersed inthe form of fine particles within the carrier material. More preferably,the drug is partially solubilized in a molten carrier material orpartially dissolved with the carrier material in a mutual solvent duringthe formulation of the microparticles. Most preferably, the drug iscompletely solubilized in the molten carrier material or completelydissolved with the carrier material in a co-solvent during theformulation of the microparticles. This is accomplished through theselection of materials and the manner in which they are processed.

Carrier materials appropriate for the fabrication of drug containingmicroparticles either dissolve slowly in water or are insoluble inwater. As used herein, the term “dissolves slowly in water” refers tomaterials that are not completely dissolved in water within a period of30 minutes. Suitable materials include fats, fatty substances, waxes,wax-like substances and mixtures thereof. Suitable fats and fattysubstances include fatty alcohols (such as lauryl, myristyl stearyl,cetyl or cetostearyl alcohol), fatty acids and derivatives, includingbut not limited, to fatty acid esters, fatty acid glycerides (mono-, di-and tri-glycerides), and hydrogenated fats. Specific examples include,but are not limited to hydrogenated vegetable oil, hydrogenatedcottonseed oil, hydrogenated castor oil, hydrogenated oils availableunder the trade name Sterotexφ, stearic acid, cocoa butter, glycerylbehenate (available under the trade name COMPRITOL 888®), glyceryldipalmitostearate (available under the trade name PRECIROL®), andstearyl alcohol. Mixtures of mono-, di- and tri-glycerides and mono- anddi-fatty acid esters of polyethylene glycol, available under the tradename GELUCIRE®) are also suitable fatty materials. Suitable waxes andwax-like materials include natural or synthetic waxes, hydrocarbons, andnormal waxes. Specific examples of waxes include beeswax, glycowax,castor wax, carnauba wax, paraffins and candelilla wax. As used herein,a wax-like material is defined as any material which is normally solidat room temperature and has a melting point of from about 30 to 300° C.

In some cases, it may be desirable to alter the rate of waterpenetration into the hydrophobic drug containing microparticles. To thisend, rate-controlling (wicking) agents may be formulated along with thefats or waxes listed above. Examples of rate-controlling materialsinclude certain starch derivatives (e.g., waxy maltodextrin and drumdried corn starch), cellulose derivatives (e.g.,hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose,and. carboxymethylcellulose), alginic acid, lactose and talc.Additionally, a pharmaceutically acceptable surfactant (for example,lecithin) may be added to facilitate the degradation and/or dissolutionof the microparticles.

Proteins which are water insoluble, such as zein, are suitable carriermaterials for the formation of drug containing microparticles.Additionally, proteins, polysaccharides and combinations thereof whichare water soluble can be formulated with drug into microparticles andsubsequently cross-linked to form an insoluble network. For example,cyclodextrins can be complexed with individual drug molecules andsubsequently cross-linked.

Certain polymers may also be used as carrier materials in theformulation of drug containing microparticles. Suitable polymers includeethylcellulose and other natural or synthetic cellulose derivatives.Polymers which are slowly soluble and form a gel in an aqueousenvironment, such as hydroxypropyl methylcellulose or polyethylene oxidemay also be suitable as carrier materials for drug containingmicroparticles.

Encapsulation or incorporation of drug into carrier materials to producedrug containing microparticles can be achieved through knownpharmaceutical formulation techniques. To create a composition thatprotects .drug from exposure upon mechanical disruption (eg, grinding,chewing, or chopping), the drug is intimately dispersed within thecarrier material. In the case of formulation in fats, waxes or wax-likematerials, the carrier material is heated above its melting temperatureand the drug is added to form a mixture containing drug particlessuspended in the carrier material, drug dissolved in the carriermaterial, or a mixture thereof. Microparticles can be subsequentlyformulated through several methods including, but not limited to,congealing, extrusion, spray chilling or aqueous dispersion. In apreferred process, one or more carrier materials are heated above itsmelting temperature, the drug is added, and the molten carriermaterial-drug mixture is congealed to form solid, spherical particlesvia a spraying or spinning cylinder or disk processes. Alternatively,the molten carrier material-drug mixture can be extruded and pelletizedto form pellets or beads. Detailed descriptions of these processes canbe found in “Remington—The science and practice of pharmacy”, 20^(th)Edition, Jennaro et. Al., (Phila, Lippencott, Williams, and Wilkens,2000, Spinning disk processes are described in U.S. Pat. Nos. 3,015,128and 7,261,529.

In a preferred process, spherical particles are produced. Sphericalparticles may introduce an additional barrier to deter tampering withthe composition. Smaller, round particles act as “ball bearings” thatare more difficult to crush or grind, and if crushed, do not allow forsignificant decrease in panicle size or surface areas of the particlesin order to effect an increase in release rate.

For compositions containing salts composed of a pharmaceutically activeagent and one or more fatty acids or amines, the salt may be formedduring the formulation process itself. To accomplish this, the one ormore fatty acids or amines are melted and mixed with the free base oracid form of the active agent at a temperature above the meltingpoint(s) of the fatty acids) or amine(s). Once a homogeneous mixture isformed, one or more additional carrier materials, such as fat, fattysubstance(s), wax or wax-like substance(s) can be added to the moltenmixture to yield a single phase composition. The molten solution is thensolidified into microparticles using one of the techniques describedabove.

The molar concentration of fatty acid or amine may need to be higherthan that of the drug in order to achieve a homogeneous single phase.For example, it has been found that, for oxycodone, a molar ratio inexcess of about 7:1 (fatty acid to drug) results in a homogeneous meltusing this technique. The molar ratio needed to obtain a homogeneousmelt may depend on the type and quantity of additional carrier materialsadded. In one embodiment, the molar ratio of fatty acid or fatty amineis from about 1:1 to about 15:1, preferably from about 6:1 to about15:1. However, molar ratios greater than 15:1, for example 15:1 to 25:1,preferably 15:1-20:1, may be required depending on the fatty acid orfatty amine, the drug to be formulated, and/or the carrier material(s).

For some carrier materials it may be desirable to use a solventevaporation technique to produce drug containing microparticles. In thiscase drug and carrier material are co-dissolved in a mutual solvent andmicroparticles can subsequently be produced by several techniquesincluding, but not limited to, forming an emulsion in water or otherappropriate media, spray drying or by evaporating off the solvent fromthe bulk solution and milling the resulting material.

In addition to modification of the drug itself, processing conditionscan be used to influence the dispersion of the drug withinwater-insoluble or slowly water soluble materials. For example, in thecase where the water in-soluble or slowly soluble material is inched andthe drug is fully or partially dissolved under stirring conditions, thetemperature, agitation rate and time of processing will influence thedegree of dissolution achieved. More specifically, a more homogenousdispersion may be achieved with a higher temperature, faster stirringrate and/or longer processing time. Ultrasound can also be applied tothe molten mixture to increase the degree of dispersion and/or the rateof dissolution of the drug.

In some embodiments, the drug in a particulate form is homogeneouslydispersed in a water-insoluble or slowly water soluble material. Tominimize the size of the drug particles within the composition, the drugpowder itself may be milled to generate fine particles prior toformulation. The process of jet milling, known in the pharmaceuticalart, can be used for this purpose. In some embodiments drug in aparticulate form is homogeneously dispersed in a wax or wax likesubstance by heating the wax or wax like substance above its meltingpoint and adding the drug particles while stirring the mixture. In thiscase a pharmaceutically acceptable surfactant may be added to themixture to facilitate the dispersion of the drug particles.

D. Coated Drug Containing Microparticles

In some embodiments, drug containing microparticles or drug particlesare encapsulated. Drug containing microparticles can be encapsulated inwater insoluble materials, slowly water soluble materials, organicinsoluble materials and/or materials with pH dependent solubilities.

In general, any coating procedure which provides a contiguous coating oneach microparticle can be used. Coating procedures known in thepharmaceutical arts include, but are not limited to, fluid bed coatingprocesses and microencapsulation may be used to obtain appropriatecoatings. Detailed descriptions of these processes can be found in“Remington—The science and practice of pharmacy”, 20^(th) Edition,Jennaro et. Al., (Phila, Lippencott, Williams, and Wilkens, 2000.

The water-insoluble coating materials may be selected from natural orsynthetic film-formers used singly, in admixture with each other, and inadmixture with plasticizers, pigments and other substances to alter thecharacteristics of the coating. A water-insoluble but water-permeablediffusion barrier may contain ethyl cellulose, methyl cellulose andmixtures thereof The water-permeable diffusion barrier may also includeammonio methacrylate copolymers sold under the trade name EUDRAGIT®(Rohm Pharma), such as EUDRAGIT RS, EUDRAGIT RL, EUDRAGIT NE andmixtures thereof. Other synthetic polymers, for example, polyvinylacetate (available under the trade name KOLLICOAT®), can also be used tofoam water-insoluble but permeable coatings.

The coating may also include a water-insoluble but enzymaticallydegradable material. In some instances the substrates of digestiveenzymes are naturally water-insoluble and can be utilized in theformulation without further processing. Solid esters of fatty acids,which are hydrolyzed by lipases, can be spray coated onto microparticlesor drug particles. Mixtures of waxes (beeswax, carnauba wax, etc.) withglyceryl monostearate, stearic acid, palmitic acid, glycerylmonopalmitate and cetyl alcohol will also form films that are dissolvedslowly or broken down in the GI tract. Zein is an example of a naturallywater-insoluble protein. It can be coated onto drug containingmicroparticles or drug particles by spray coating or by wet granulationtechniques. In addition to naturally water-insoluble materials, somesubstrates of digestive enzymes can be treated with cross-linkingprocedures, resulting in the formation of non-soluble networks. Manymethods of cross-linking proteins, initiated by both chemical andphysical means, have been reported. In some embodiments, chemicalcross-linking agents are used. Examples of chemical cross-linking agentsinclude aldehydes (gluteraldehyde and formaldehyde), epoxy compounds,carbodiimides, and genipin. In addition to these cross-linking agents,oxidized and native sugars have been used to cross-link gelatin(Cortesi, R., et al., Biomaterials 19 (1998) 1641-1649). Cross-linkingcan also be accomplished using enzymatic means; for example,transglutaminase has been approved as a GRAS substance for cross-linkingseafood products. Finally, cross-linking can be initiated by physicalmeans such as thermal treatment, UV irradiation and gamma irradiation.

To produce a coating layer of cross-linked protein surrounding drugcontaining microparticles or drug particles, a water soluble protein canbe spray coated onto the microparticles and subsequently cross-linked byone of the methods described above. Alternatively, drug containingmicroparticles can be microencapsulated within protein bycoacervation-phase separation (for example, by the addition of salts)and subsequently cross-linked. Some suitable proteins for this purposeinclude gelatin, albumin, casein, and gluten.

Polysaccharides can also be cross-linked to form a water-insolublenetwork. For many polysaccharides, this can be accomplished by reactionwith calcium salts or multivalent cations which cross-link the mainpolymer chains. Pectin, alginate, dextran, amylose and guar gum aresubject to cross-linking in the presence of multivalent cations.Complexes between oppositely charged polysaccharides can also be formed;pectin and chitosan, for example, can be complexed via electrostaticinteractions. Insoluble coatings can be formed on particles in thisfashion. It should be noted that in many cases polysaccharides arebroken down specifically by enzymes produced by bacteria within thecolon.

In some cases a water-insoluble but enzymatically degradable coatingincluding both a protein and a polysaccharide can be produced if thecomponents are oppositely charged polyelectrolytes. Under the propertemperature, pH, and concentrations, the two polymers can interactthrough their opposite electrical charges and form a water-insolublecomplex. If a core particle is present at the time the complex phaseseparates, it will be coated. For example, gelatin and gum arabic can becoated onto a core particle utilizing this process. Optionally, thecomplex can be made irreversibly insoluble by subsequent cross-linkinginduced by chemical or physical means.

Coating materials may also include a pH sensitive polymer which isinsoluble in the acid environment of the stomach, and soluble in themore basic environment of the GI tract. These coatings, referred to asenteric coatings, create a dosage form designed to prevent drug releasein the stomach. Preventing drug release in the stomach has the advantageof reducing side effects associated with irritation of the gastricmucosa and/or of minimizing exposure of drug to very low pH. Avoidingrelease within the stomach can be achieved using enteric coatings knownin the art. The enteric coated formulation remains intact orsubstantially intact in the stomach, however, once the formulationreaches the small intestines, the enteric coating dissolves and exposeseither drug-containing carrier particles or drug-containing carrierparticles coated with extended release coating.

Enteric coated particles cab be prepared as described in “Pharmaceuticaldosage form tablets”, eds. Liberman et. al. (New York, Marcel Dekker,Inc., 1989), “Remington—The science and practice of pharmacy”, 20th ed.,Lippincott Williams & Wilkins, Baltimore, Md., 2000, and “Pharmaceuticaldosage forms and drug delivery systems”, 6th Edition, Ansel et.al.,(Media, Pa.: Williams and Wilkins, 1995). Examples of suitable coatingmaterials include, but are not limited to, cellulose polymers, such ascellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropylmethylcellulose phthalate and hydroxypropyl methylcellulose acetatesuccinate; polyvinyl acetate phthalate, acrylic acid polymers andcopolymers, and certain methacrylic resins that are commerciallyavailable under the trade name EUDRAGIT® (Rohm Pharma). Additionally thecoating material may contain conventional carriers such as plasticizers,pigments, colorants, glidants, stabilization agents, and surfactants.

In some cases it may be desirable to coat the particles with a coatingwhich is soluble in aqueous solutions but insoluble in hydroalcoholicsolutions. In this case the coating material may or may not have pHsensitive solubility in aqueous solutions.

In other cases it may be desirable to combine coating materials toproduce a tailored release of drug. For example, combinations ofinsoluble polymers and pH dependent polymers can produce a pH dependentsustained release profile. Combinations of insoluble polymers (eg,ethylcellulose), water-soluble polymers (eg, HPMC or PEG) and pHdependent swellable polymers (eg, carboxyvinylpolymer) have also beenreported to produce pH dependent sustained release profiles (See, forexample, Journal of Controlled Release, 2006, 111:309-315).

In one embodiment, the particles are coated with cellulose acetatephthalate. Cellulose acetate phthalate is typically used as an entericcoating.

E. Antioxidants

In some embodiments, the composition includes one or more anti-oxidants.Suitable antioxidants include, but are not limited to, butylatedhydroxytoluene (BHT); ascorbic acid, its salts and esters; Vitamin E,tocopherol and its salts; sulfites such as sodium metabisulphite;cysteine and its derivatives; citric acid; propyl gallate, and butylatedhydroxyanisole (BHA).

Antioxidants may be necessary to prevent oxidative degradation of theactive pharmaceutical ingredient and/or the one or more inactive carriermaterials in the composition. Oxidation of one or more components mayoccur during the formulation process itself or during the shelf-life ofthe composition. Oxidation may result from exposure to the oxygencontent of air or, alternatively, may be related to impurities in thecarrier materials. For example, highly reactive species such asperoxides, superoxides, hypochlorites and formic acid may be present incarrier materials as manufacturing-related impurities. Also, trace metalimpurities in carrier materials, such as iron and copper, can catalyzeoxidation reactions. An antioxidant may be included in the compositionto mitigate the degradation of the drug in such cases. If the source ofoxidation is a reactive manufacturing-related impurity in one or more ofthe carrier materials, the anti-oxidant can be co-melted with thecarrier materials prior to the introduction of the drug into theformulation in order to protect the drug from these reactive species.

The concentration of the antioxidant is generally from about 0.001% toabout 1% w/w, preferably from about 0.01% to about 0.5% w/w. However,concentrations of less than 0.001% or greater than 0.5% may be used,provided the concentration is sufficient to stabilize the formulationand is non-toxic.

F. Dosage Forms

In one embodiment a drug is partially dissolved within a water-insolubleor slowly water soluble material during the manufacturing process, forexample, by mixing at a temperature above the melting point of thecarrier material, and the mixture is formulated into microparticles. Inanother embodiment a drug is fully dissolved within a water-insoluble orslowly water soluble material during the manufacturing process, forexample, by mixing at a temperature above the melting point of thecarrier material, and the mixture is formulated into microparticles. Instill a further embodiment, the drug containing microparticles, wherethe drug is homogeneously dispersed in a particulate form, or has beenpartially or fully dissolved within the carrier material during themanufacturing process, are coated with one or more coatings to formcoated microparticles. In a further embodiment, drug particles arecoated directly with one or more coatings to form coated microparticles.

The microparticles, coated microparticles, or a mixture thereof areformed into a solid dosage form suitable for oral administration. Forexample, microparticles or coated microparticles can be incorporatedinto hard shell capsules, dispersed within a soft gelatin capsule, orcombined with appropriate excipients such as magnesium stearate aslubricant, colloidal silicon dioxide as glidant, sodium starchglycolide, sodium croscarmellose or crospovidone as disintegrant, sodiumdodecyl sulfate or Polyoxyethylene (20) sorbitan monoleate, polyvinylpyrrolidone or hydroxypropylmethylcellulose as crystallizationinhibitor, and lactose and microcrystalline cellulose as fillers, andtableted by compression.

In some embodiments, the compositions are coated with an entericcoating. Enteric coatings known in the art are applied directly to theabuse-deterrent microparticle or coated microparticle compositions orare applied to the surface of a capsule or tablet containing the abusedeterrent microparticle and/or coated microparticle compositions.Enteric coatings known in the art include, for example, acrylic polymersthat are commercially available under the trade name EUDRAGIT®,cellulose acetate phthalate, hydroxypropylmethyl-cellulose phthalate,polyvinylacetate phthalate, shellac, hydroxypropylmethylcellulosesuccinate, cellulose acetate trimelliate or mixtures thereof. In oneembodiment, the particles are coated with cellulose acetate phthalate.

Dosage forms can include one or more drugs. When the dosage formincludes two or more drugs they can be Scheduled drugs or can be acombination of Scheduled and non-Scheduled drugs. The drugs can beincorporated into separate microparticle compositions where theScheduled drugs are incorporated into abuse deterrent microparticlecompositions and the non-Scheduled drugs are incorporated into abusedeterrent microparticle compositions, sustained release compositionsknown in the art or immediate release compositions known in the art. Thecompositions containing the different drugs are formulated into a singlesolid dosage form suitable for oral administration, for example, theycan be incorporated into a gelatin capsule, or combined with appropriateexcipients and compressed into a tablet form. Examples of non-scheduleddrugs that may be included in dosage forms described herein include, butare not limited to, aspirin, acetaminophen, non-steroidalanti-inflammatory drugs, cyclooxygenase II inhibitors,N-methyl-D-aspartate receptor antagonists, glycine receptor antagonists,triptans, dextromethorphan, promethazine, fiorinal guaifenesin,butalbital, and caffeine.

An immediate release dose can be incorporated into the formulation inseveral ways. Immediate release microparticles can be made utilizingstandard methodologies and formulated along with abuse-deterrentmicroparticle and/or coated microparticle compositions in a suitableoral dosage form. Alternatively, a coating containing drug which isavailable for immediate release can be placed on a tablet containingabuse-deterrent microparticle and/or coated microparticle compositionsplus appropriate excipients. Additionally, an immediate dose of drug canbe granulated or blended with rapidly dissolving excipients andsubsequently compressed (1) as one layer of bi-layer tablets in whichthe abuse-deterrent microparticle and/or coated microparticlecompositions are compressed as the other layer, or (2) as the outerlayer of compression-coated tablets in which the abuse-deterrentmicroparticle and/or coated microparticle compositions are compressed asthe inner core, or (3) into tablets in which abuse-deterrentmicroparticle and/or coated microparticle compositions are embedded.

In some embodiments, the immediate release portion of the dosage formcontains a lipophilic drug derivative. For example, salt derivatives orcomplexes that are insoluble at a neutral pH but dissociate, therebyreleasing the parent compound, at an acidic pH are ideal for immediaterelease within the stomach. In the case of oxycodone some salts that mayexhibit this property include, but are not limited to, the tannate,phthalate, salicylate, gallate, pectinate, phytate, saccharinate,asesulfamate and terephthalate salts. Complexes of drug with one or moremetal ions and, optionally, one or more lipophilic counter-ions may alsobe used for immediate drug release. Use of salts or complexes in theimmediate release portion of the dosage form reduces the abuse potentialof the immediate release dose if the formulation is crushed and (1)snorted or (2) dissolved in water since these salts will be poorlysoluble under these conditions. It is understood by the one of ordinaryskill in the art that such salts or complexes may also be used toformulate an immediate release dosage form without a sustained releaseportion.

Additional mechanisms to reduce the potential for abuse can also beincorporated during the process of formulating tablets. For example,ingredients can be added to deter chewing or snorting of the finalformulation. For example, an intensely bitter substance may deterchewing, while an intensely spicy ingredient, such as capsaicin, maydeter snorting. The addition of a colored dye, which would stain theskin and mucosal surface of the nose following snorting may also serveto reduce this practice.

Optional excipients present in the oral dosage form containing abusedeterrent microparticles or coated microparticles include, but are notlimited to diluents, binders, lubricants, disintigrants, colorants,plasticizers and the like. Diluents, also termed “fillers,” aretypically necessary to increase the bulk of a solid dosage form so thata practical size is provided for compression of tablets. Examples ofdiluents include cellulose, dry starch, microcrystalline cellulose,dicalcium phosphate, calcium sulfate, sodium chloride confectioner'ssugar, compressible sugar, dextrates, dextrin, dextrose, sucrose,mannitol, powdered cellulose, sorbitol, and lactose. Binders are used toimpart cohesive qualities powdered materials and can include materialssuch as starch, gelatin, sugars, natural and synthetic gums,polyethylene glycol, ethylcellulose, methylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose, waxes andpolyvinyl pyrrolidone. Lubricants are used to facilitate tabletmanufacture; examples of lubricants include talc, magnesium stearate,calcium stearate, hydrogenated vegetable oils stearic acid, sodiumstearyl fumarate, sodium benzoate, sodium acetate, leucine, sodiumoleate, sodium lauryl sulfate, magnesium lauryl sulfate and polyethyleneglycol. Disintegrants can be added to pharmaceutical formulations inorder to facilitate “breakup” or disintegration after administration.Materials used for this purpose include starches, clays, celluloses,aligns, gums, and cross-linked polymers. A plasticizer may be includedin coating materials to alter their mechanical properties. Examples ofplasticizers include benzyl benzoate, chlorobutanol, dibutyl sebacate,diethyl phthalate, glycerin, mineral oil, polyethylene glycol, sorbitol,triacetin, triethyl citrate, glycerol, etc. In addition to the additivesabove, coloring and flavoring agents may also be incorporated into thecomposition.

II. Methods of Administration

In addition to providing a deterrent to common methods ofabuse/diversion, the formulation can provide a sustained release of drugover an extended time period. This is a natural consequence of the factthat, in the present formulation, drug is slowly released from apredominantly water-insoluble, hydrophobic matrix as it passes throughthe GI tract. The barrier components may be degraded as the matrixpasses through the GI tract, for example, by enzymes, the surfactantaction of bile acids and mechanical erosion.

In some embodiments, an immediate release of drug is achieved within thestomach in order to provide rapid therapeutic onset.

The pharmaceutical drug composition is administered orally. Theappropriate dosage formulations can be obtained by calculation of thepharmacokinetics of the formulation, then adjusting using routinetechniques to yield the appropriate drug levels based on the approveddosage forms. Any suitable amount of drug containing microparticles orcoated microparticles can be included in the final formulation. Theselection of a suitable amount of drug containing microparticles dependson the dosage desired and is readily determined by those skilled in theart.

In addition to oral administration, some embodiments may also beadministered by other routes, including, but not limited to, rectal andnasal administration. Some embodiments may also be suitable forformulation as oral liquids.

The present composition and method of making and using the compositionwill be further understood by reference to the following non-limitingexamples.

EXAMPLES Example 1 Preparation of Drug Containing Microparticles

TABLE 1 Compositions Composition Composition Composition Composition ofof of of Formulation Formulation Formulation Formulation Ingredient A BC D Oxycodone  5 g  5 g 10 g  5 g Base Myristic Acid — — 50 g 30 gStearic Acid 34 g 34 g — — Yellow 10 g — 10 g 10 g Beeswax Carnauba wax 5 g 10 g 20 g 10 g

Procedure:

-   1. Fatty acid (myristic or stearic acid) was melted in an erlenmeyer    flask in a silicone oil bath at 100° C. The mixture was stirred and    kept, under an argon blanket for this and all subsequent steps.-   2. Oxycodone base was introduced into the molten fatty acid and the    melt was stirred until the oxycodone base was completely dissolved    and a clear liquid was formed.-   3. Yellow beeswax was added and dissolved under constant stirring.-   4. Carnauba wax was added and dissolved under constant stirring.-   5. The resulting homogeneous molten solution was poured onto    aluminum foil and allowed to solidify at room temperature.-   6. The bulk material obtained was combined with small quantities of    dry ice and subjected to size reduction in a mortar and pestle.-   7. The dry ice was allowed to dissipate and the particles were    sieved to obtain various size ranges. Particles 20-40 mesh in size    (400-841 micron) were subjected to testing.

Example 2 Release of Drug from Crushed Microparticles

In vitro testing was conducted in order to assess the influence ofcrushing of the microparticles produced in Example 1 on the release insimulated stomach conditions. A currently marketed sustained releaseformulation of oxycodone, OxyContin®, was also subjected to crushing anddissolution for comparison purposes.

Microparticles (Formulations A, B, C or D, all 20-40 mesh in startingparticle size) or tablets were crushed using a glass mortar & pestle.The resulting crushed material was placed in a dissolution vesselequipped with paddles (USP Apparatus II). 900 mL of 0.1N HCl pre-warmedto 37° C. was added to the vessels and stirred for 15 minutes. After 15minutes the amount of oxycodone released was determined. The results areshown in Table 2.

TABLE 2 Drug Release from Crushed Compositions % Released in 15 minutesin 0.1N HCl Sample (n = 3) Oxycontin ® 95.6 +/− 2.7 (40 mg Tablet)Formulation A 31.6 +/− 2.6 (microparticles containing 40 mg oxycodoneHCl equivalent) Formulation B 19.7 +/− 1.4 (microparticles containing 40mg oxycodone HCl equivalent) Formulation C 14.8 +/− 1.1 (microparticlescontaining 20 mg oxycodone HCl equivalent) Formulation D 18.2 +/− 1.6(microparticles containing 20 mg oxycodone HCl equivalent)

As illustrated in the table above, the microparticle compositions ofExample 1 release only a fraction of the total drug load in simulatedstomach conditions when crushed. In contrast, a currently marketedsustained release composition, OxyContin®, releases approximately 96% ofthe drug load when crushed and exposed to identical conditions.

Example 3 Preparation of Oxycodone Containing Microparticles Using aSpinning Disk Atomization Process

Batch size: 1000 g

Component Quantity (g)/Batch Oxycodone base 91 Myristic acid 545 Beeswax182 Carnauba Wax 182 Total 1000.0

Procedure:

-   1. Myristic acid was melted at 85° C. in a silicone oil bath while    constantly flowing argon above the surface of the solution.-   2. Beeswax was added to the molten fatty acid and mixed until a    clear, homogeneous solution was obtained.-   3. Carnauba wax was added to the molten solution and mixed until a    clear, homogeneous solution was obtained.-   4. Oxycodone base was added to the molten solution and mixed until a    clear, homogeneous solution was obtained.-   5. The resulting molten solution was transferred to a feed kettle    and continuously metered onto a spinning disk atomizer in order to    form solid, spherical microparticles.

Example 4 Preparation of Coated Drug Containing Microparticles

The drug-containing particles from Example 3 can be spray coated withcellulose acetate phthalate

Example 5 Preparation of Oxymorphone Containing Microparticles

Batch size: 630.6 g

Component Quantity (g)/Batch Oxymorphone base 60 Stearic Acid 420Beeswax 30 Carnauba Wax NF 120 Butylated Hydroxyanisole 0.6 Total 630.6

Procedure:

-   1. Stearic acid was melted in an erlenmeyer flask in a silicone oil    bath at 100° C. Note the composition was subjected to stirring and    was kept under an argon blanket for this and all subsequent steps.-   2. Butylated hydroxyanisole was added to the molten stearic acid    while mixing.-   3. Oxymorphone base was introduced into the molten fatty acid and    the melt was stirred until all oxymorphone base dissolved and a    clear liquid was formed.-   4. Beeswax was added and dissolved under constant stirring.-   5. Carnauba wax was added and dissolved under constant stirring.-   6. The resulting homogeneous molten solution was poured onto    aluminum foil and allowed to solidify at room temperature.-   7. The bulk wax obtained was combined with dry ice and subjected to    size reduction in a mortar and Pestle.-   8. The dry ice was allowed to dissipate and the particles were    sieved to obtain particles in the 40-80 mesh size range.

Example 6 Preparation of Capsules for Oral Administration

The drug containing microparticles from Examples 1, 3, 4, or 5 can beblended with a lubricant and incorporated into standard hard gelatincapsules

We claim:
 1. An orally administrable abuse-deterrent pharmaceuticalcomposition comprising a therapeutically effective amount ofmicroparticles comprising (a) a lipophilic drug prone to abuse orlipophilic derivative of a drug prone to abuse, and (b) one or morecarrier materials selected from the group consisting of fats, fattysubstances, waxes, wax-like substances and mixtures thereof, wherein thedrug is dispersed within the one or more carrier materials, and therelease of a portion of incorporated drug is retarded when the physicalintegrity of the composition is compromised and the compromisedcomposition is exposed to water.
 2. An orally administrableabuse-deterrent pharmaceutical composition comprising a therapeuticallyeffective amount of microparticles comprising (a) a lipophilicderivative of a drug prone to abuse (b) one or more carrier materialswhich either dissolve slowly in water or are insoluble in water, andwherein the lipophilic derivative of the drug is dispersed within theone or more carrier materials which are either slowly soluble in wateror insoluble in water, and wherein the release of a portion ofincorporated drug is retarded when the physical integrity of thecomposition is compromised and the compromised composition is exposed towater.
 3. The composition of claim 1 or 2 wherein the composition is acontrolled-release pharmaceutical composition.
 4. The composition ofclaim 1 or 2 wherein the drug prone to abuse is selected from the groupconsisting of 1-phenylcyclohexylamine,1-piperidinocyclohexanecarbonitrile, alfentanil, alphacetylmethadol,alphaprodine, alprazolam, amobarbital, amphetamine, anileridine,apomorphine, aprobarbital, barbital, barbituric acid derivative,bemidone, benzoylecgonine, benzphetamine, betacetylmethadol;betaprodine, bezitramide, bromazepam, buprenorphine, butabarbital,butalbital, butorphanol, camazepam, cathine, chloral, chlordiazepoxide,clobazam, clonazepam, clorazepate, clotiazepam, cloxazolam, cocaine,codeine, chlorphentermine, delorazepam, dexfenfluramine, dextromoramide,dextropropoxyphen, dezocine, diazepam, diethylpropion, difenoxin,dihydrocodeine, dihydromorphine, dioxaphentyl butyrate, dipanone,diphenoxylate, diprenorphine, ecgonine, enadoline, eptazocine,estazolam, ethoheptazine, ethyl loflazepate, ethylmorphine, etorphine,femproponex, fencamfamin, fenfluramine, fentanyl, fludiazepam,flunitrazepam, flurazepam, glutethimide, halazepam, haloxazolam,hexalgon, hydrocodone, hydromorphone, isomethadone, hydrocodone,ketamine, ketazolam, ketobemidone, levanone, levoalphacetylmethadol,levomethadone, levomethadyl acetate, levomethorphan, levorphanol,lofentanil, loperamide, loprazolam, lorazepam, lormetazepam, lysergicacid, lysergic acid amid; mazindol, medazepam, mefenorex, meperidine,meptazinol, metazocine, methadone, methamphetamine, methohexital,methotrimeprazine, methyldihydromorphinone, methylphenidate,methylphenobarbital, metopon, morphine, nabilone, nalbuphine, nalbupine,nalorphine, narceine, nefopam, nicomorphine, nimetazepam, nitrazepam,nordiazepam, normethadone, normorphine, oxazepam, oxazolam, oxycodone,oxymorphone, pentazocine, pentobarbital, phenadoxone, phenazocine,phencyclidine, phendimetrazine, phenmetrazine, pheneridine, piminodine,prodilidine, properidine, propoxyphene, racemethorphan; racemorphan,racemoramide, remifentanil, secobarbital, sufentanil, talbutal,thebaine, thiamylal, thiopental, tramadol, trimeperidine, vinbarbital,allobarbitone, alprazolam, amylobarbitone, aprobarbital, barbital,barbitone, benzphetamine, brallobarbital, bromazepam, brotizolam,buspirone, butalbital, butobarbitone, butorphanol, camazepam,captodiame, carbromal, carfentanil, carpipramine, cathine, chloral,chloral betaine, chloral hydrate, chloralose, chlordiazepoxide,chlorhexadol, chlormethazole edisylate, chlormezanone, cinolazepam,clobazam, potassium clorazepate, clotiazepam, cloxazolam,cyclobarbitone, delorazepam, dexfenfluramine, diazepam, diethylpropion,difebarbamate, difenoxin, enciprazine, estazolam, ethyl loflazepate,etizolam, febarbamate, fencamfamin, fenfluramine, fenproporex,fluanisone, fludiazepam, flunitraam, flunitrazepam, flurazepam,flutoprazepam, gepirone, glutethimide, halazepam, haloxazolam,hexobarbitone, ibomal, ipsapirone, ketazolam, loprazolam mesylate,lorazepam, lormetazepam, mazindol, mebutamate, medazepam, mefenorex,mephobarbital, meprobamate, metaclazepam, methaqualone, methohexital,methylpentynol, methylphenobarbital, midazolam, milazolam, morphine,nimetazepam, nitrazepam, nordiazepam, oxazepam, oxazolam, paraldehyde,pemoline, pentabarbitone, pentazocine, pentobarbital, phencyclidine,phenobarbital, phendimetrazine, phenmetrazine, phenprobamate,phentermine, phenyacetone, pinazepam, pipradol, prazepam, proxibarbal,quazepam, quinalbaritone, secobarbital, secbutobarbitone, sibutramine,temazepam, tetrazepam, triazolam, triclofos, zalepan, zaleplon,zolazepam, zolpidem, and zopiclone.
 5. The composition of claim 1 or 2wherein the lipophilic derivative of a drug is a free base or a freeacid of the drug.
 6. The composition of claim 1 or 2 wherein thelipophilic derivative of a drug is a salt comprising the ionized drugand a lipophilic counter-ion.
 7. The composition of claim 1 or 2 whereinthe lipophilic derivative of a drug is a salt comprising the ionizeddrug and a one or more fatty acids.
 8. The composition of claim 2wherein the microparticles consist of drug dispersed in one or morecarrier materials selected from the group consisting of fats, fattysubstances, waxes, wax-like-substances and combinations thereof.
 9. Thecomposition of claim 8 wherein the microparticles consist of drugdispersed in a fat or a fatty substance.
 10. The composition of claim 2wherein the microparticles consist of a drug dispersed in a carriermaterial selected from the group consisting of fats, waxes, naturalpolymers, synthetic polymers or a mixture thereof.
 11. The compositionof claim 1 or 2 wherein the individual microparticles are coated withone or more independent layers.
 12. The composition of claim 1 or 2wherein the drug prone to abuse is co-administered with a drug that hasno appreciable abuse potential.
 13. The composition of claim 1 or 2wherein the drug prone to abuse is oxycodone.
 14. The composition ofclaim 1 or 2 wherein the drug or drug derivative is dissolved in thecarrier material in a molten state to result in a uniform dispersionwithin the carrier material.
 15. The composition of claim 1 or 2 whereinthe drug or drug derivative is dissolved in a co-solvent along with acarrier material to result in a uniform dispersion within the carriermaterial.
 7. composition of claim 7 wherein the fatty acid is selectedfrom the group consisting of stearic acid, palmitic acid, myristic acid,and mixtures thereof.
 17. The composition of claim 1 or 2 wherein one ormore carrier materials is selected from the group consisting of stearicacid, palmitic acid, myristic acid, beeswax, carnauba wax, hydrogenatedoil, and mixtures thereof.
 18. The composition of claim 1 or 2, whereinthe individual microparticles are further formulated into a tablet orcapsule for oral administration.
 19. The composition of claim 4 whereinthe drug prone to abuse is selected from the group consisting ofoxycodone, oxymorphone, hydrocodone, hydromorphone, morphine, tramadol,methylphenidate, and amphetamine.
 20. The composition of claim 1 or 2,wherein the composition further comprises an antioxidant.
 21. Thecomposition of claim 20, wherein the antioxidant is selected from thegroup consisting of butylated hydroxy anisole (BHT); ascorbic acid, itssalts and esters; Vitamin B, tocopherol and its salts; sulfites such assodium metabisulphite; cysteine and its derivatives; citric acid; propylgallate; butylated hydroxyanisole (BHA); and combinations thereof. 22.The composition of claim 20, wherein the concentration of theantioxidant is from about 0.001% to about 1% w/w.
 23. The composition ofclaim 22, wherein the concentration of the antioxidant is from about0.01% to about 0.5% w/w.
 24. The composition of claim 1 or 2 wherein themicroparticles are less than 1000 micron in diameter.
 25. Thecomposition of claim 1 or 2 wherein the microparticles are spherical.26. A method of manufacturing the abuse-resistant pharmaceuticalcomposition of claim 1 or 2, the method comprising homogeneouslydispersing a therapeutically effective amount of a lipophilic drug proneto abuse or a lipophilic derivative of a drug prone to abuse, in one ormore one or more carrier materials, wherein the release of a portion ofincorporated drug is retarded when the physical integrity of thecomposition is compromised and the compromised composition is exposed towater.
 27. The method of claim 26, further comprising incorporating oneor more antioxidants into the composition.
 28. A method of administeringan abuse-resistant pharmaceutical composition comprising orallyadministering to a patient in need thereof an abuse-deterrentpharmaceutical composition comprising a therapeutically effective amountof a lipophilic drug prone to abuse or a lipophilic derivative of a drugprone to abuse, wherein the drug is homogeneously dispersed one or moreone or more carrier materials, and wherein the release of a portion ofincorporated drug is retarded when the physical integrity of thecomposition is compromised and the compromised composition is exposed towater.
 29. The method of claim 28, wherein the composition furthercomprises one or more antioxidants.